Telomerase and the

consequence of telomere
dysfunction
AAAS
Annual meeting
February 19th 2010

Carol Greider
Daniel Nathans Professor
& Director Department of Molecular
Biology and Genetics
Johns Hopkins University
School of Medicine

Telomeres and Telomerase:

Bridging Science and Society
Curiosity driven research establishes
fundamental knowledge that fuels
practical applications.

Telomeres are the ends of

chromosomes

Protect ends

Maintain length

Tetrahymena thermophila: single

celled animal with 40,000
chromosomes

Elizabeth Blackburn & Joe

Gall (1978):
Defined telomere
sequence as tandem
repeats of TTGGGG

TTGGGG

Replication

Replication

Replication

Tetrahymena and yeast: conservation

of telomere function & telomere
elongation
Telomere

Ori

Marker

Maintain linear
plasmid in yeast

Remove right telomere

Add yeast genomic DNA
Yeast telomeres stabilizes
linear plasmid

Nature July 1984

Telomerase activity
identified

Telomerase allows telomere length

equilibrium maintenance
TR
Replication

Telomerase
TERT

Why does telomerase matter?

It is required for cells that must divide many
times
Cancer

Tissue renewal

Telomere shortening in cellular

senescence

Nature May 1990

Telomeres shorten with age

Telomerase
is limiting in
cells

Vaziri et al. AJHG (1995)

Using laboratory mice to probe

telomere function

Telomerase knockout mouse

mTR+/ mTR+/ +

mTR+/ -

mTR+/ -

mTR- / -

G1

G1
G2

G2
G3

G3
G4

G4
G5

Cell death
or
Senescence

G5
G6

G6

Blasco et al. Cell 1997

Quantitative analysis of telomere

length

Telomeres shorten progressively in

telomerase-null mice
mTR+/ -

mTR+/ -

mTR- / - (G1)

G1

G2

G2

G3

G3

G4

G4

G5

G5
G6

Blasco et al. Cell 1997

Loss of telomere sequence leads to

loss of telomere function

WT

KO-G2

KO-G4

KO-G6

The consequences of short

telomeres
mTR+/ mTR+/ +

mTR+/ -

mTR+/ -

mTR- / -

G1

G1
G2

G2
G3

G3
G4

G4
G5

Cell death
or
Senescence

G5
G6

G6

Telomere shortening leads to cell

death
Replication

Replication

Replication

Cell Death

Short telomeres limit cell growth

Cancer

Tissue renewal

Nature 2001

Dyskeratosis congentia causes bone

marrow failure
Skin and nail problems
Skin hyperpigmentation
Rashes
Abnormal nail growth
Mortality
Bone marrow failure
Cancer
other?

TERT mutations cause autosomal

dominant inheritance of dyskeratosis
congentia
Hopkins Family 1

I1

Genetic anticipation.
Affected people are
heterozygous for hTR or
hTERT mutations.

II 1

III 1

Dominant negative or
haploinsufficiency?

Armanios et al. PNAS

(2005)

Cast/Ei mice have short telomeres

similar to humans

Bred mTR null

allele onto Cast/Ei
background

Hemann & Greider NAR

Progressive telomere shortening

during mTR+/- breeding
mTR+/ -

mTR+/ -

HG1

HG1

HG2

HG2

HG3

HG3

HG4

HG5

HG4

Short telomeres in CAST/EiJ mTR+/mice

Telomerase
is limiting in
cells

Hao et al. Cell

2005

Telomere shortening at each mTR+/generation affects survival of

offspring
mTR+/ -

mTR+/ -

HG1

HG1

HG2

HG2

HG3

HG3

HG4

WT5*

HG5

HG4

KO(G5)

Decreased survival of mTR-/- from

later generation heterozygous
crosses
WT
Percent survival

100

KO from HG3 parents

KO from HG6 parents
KO from HG8 parents

75
50
25
0

100

200

300

400

Days

Inheritance of short telomeres decreases survival.

Resembles genetic anticipation in dyskeratosis congenita.
Armanios et al. AJHG
2009

Telomere shortening during mTR+/breeding affects wildtype offspring

mTR+/ -

mTR+/ -

HG1

HG1

HG2

HG2

HG3

HG3

HG4

WT5*

HG5

HG4

KO(G5)

Short telomeres in Wt5* mice

HG4

KO

HG4

HG5

WT5*

Hao et al. Cell

2005

Short telomeres cause phenotypes in

Wt* mice
TESTIS APOPTOSIS

SPLEEN
WEIGHT
Corrected
Spleen
Weight
7
6
5
4
3
2
1
0

wt (n=6)

wt8*1 (n=7)

Genetic disease in the absence of telomerase

mutation (Occult genetic disease)

ko (n=9)

Wt* mice reestablish telomere

equilibrium after several generations
mTR+/ - HG4

mTR+/ - HG4

mTR+/ + WT5*1

mTR+/ +WT5*1

mTR+/ +WT5*2

mTR+/ +WT5*2

mTR+/ +WT5*3
mTR+/ +WT5*4

mTR+/ +WT5*3
mTR+/ +WT5*4

Telomerase is limiting in
Armanios et al. AJHG
cells

Reestablishment of telomere length

equilibrium rescues testes
phenotype

Armanios et al. AJHG (2009)

Telomere shortening implicated in

several diseases
Hopkins Family 1
I1

II 1

III 1

Short telomeres in lung disease

NEJM 357 p1317

(2007)

Many diseases seen in families with

insufficient telomerase share
features of age-related disease

Syndromes of telomere shortening:

the tip of the iceberg

Wide distribution of telomere length

in the human population

Valdes et al, 2005 Lancet

(2005)

Bridging Science and Society:

Understanding of telomeres came from
curiosity about chromosome maintenance

Summary and implications

Telomeres are required for chromosome end

protection.

Telomerase is essential for telomere

maintenance.

Telomere shortening leads to cell death or

senescence after many cell divisions.

Short telomeres limit tissue renewal.

Telomere length may predict onset of certain age

related diseases.

Fundamental discoveries lead to clinical applications

Greider Lab
Telomere length regulation
Vinny Raganathan
Sofia Vidal-Cardenas
Carla Connely
Response to telomere
dysfunction
Nini Guo
Margaret Strong
Tammy Morrish

Collaborators
Oncology
Mary Armanios
Jonathan Alder
Erin Parry
Pathology
Baktiar Karim
David Huso

New discoveries come from unlikely places

Telomere length predicts mortality

rate

Cawthon et al. Lancet